Dieseas research:

Malaria:
We are part of a collaborative project headed by Austin Burt at Imperial College in London that is one of the Gates Foundation "Grand Challenge Projects in Global Health". Malaria is caused by a parasite that spends part of its life cycle inside the mosquito, and is passed along to humans by mosquito bites. The idea behind the project is to make mosquitoes resistant to the parasite by eliminating genes required in the mosquito for the parasite to live. Our part of the project is to use our computer based design methods (ROSETTA) to engineer new enzymes that will specifically target and inactivate these genes.

Anthrax:
We are using ROSETTA to help John Collier's research group at Harvard build models of anthrax toxin that should contribute to the development of treatments. You can read the abstract of a paper describing some of this work at

HIV:
One of the reasons that HIV is such a deadly virus is that it has evolved to trick the immune system. We are collaborating with researchers in Seattle and at the NIH to try to develop a vaccine for HIV. Our role in this project is central--we are using ROSETTA to design small proteins that display the small number of critical regions of the HIV coat protein in a way that the immune system can easily recognize and generate antibodies to. Our goal is to create small stable protein vaccines that can be made very cheaply and shipped all over the world.

Other viruses:
We have been collaborating with Pam Bjorkman's laboratory at Cal Tech to use the ROSETTA protein-protein docking methodology to build models of herpes simplex virus proteins in complex with human proteins.

Alzheimer's disease:
Alzheimer's and many other diseases are likely to be caused by abberant protein folding in which proteins form large aggregated structures called amyloids rather than folding up into their normal biologically active states. A big advance was made recently by David Eisenberg's research group at UCLA in solving the first structure of an amyloid. We are collaborating with their research group to use the structure to predict which parts of proteins are likely to form amyloids, which will be a first step to blocking amyloid formation and hopefully disease.

Cancer:
Cancer can be caused by mutations in key genes that disrupt normal cellular control processes. We are developing methods for cutting DNA at specific sites in the genome, and we will be targeting sites that are implicated in cancer. After these sites are cut, they should be repaired by the cell using a second, unmutated copy of the gene and the cell should no longer be cancerous. This is a very specific form of gene therapy that, if successful, will circumvent one the main objections to current gene therapy methods; namely, current methods insert the unmutated copy of a gene randomly into the genome, and if the insertion point happens to be near an oncogene, the gene therapy will cure one disease but cause another. Because our methods will target specific sites instead of random sites, they should avoid this pitfall.


Prostate Cancer:
The androgen receptor (AR) binds testosterone and is responsible for normal male development. When the AR becomes hypersensitive to testosterone, prostate cancer is the result. The current treatment for prostate cancer, called "hormone therapy", involves lowering the amount of testosterone available (sometimes by castration). Many malignant tumors are resistant to this therapy, however, so we are applying our protein design methodology to find different ways to inhibit the AR and to treat prostate cancer. Specifically, we are trying to design proteins that will disable the AR even in the presence of testosterone. We are doing this by designing proteins that will prevent the AR from entering the nucleus of the cell (which is where it does its dirty work), and also preventing it from binding DNA and activating tumor-specific genes even if it does get into the nucleus.